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CN101035531A - Halogenated benzamide derivatives - Google Patents

Halogenated benzamide derivatives Download PDF

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Publication number
CN101035531A
CN101035531A CNA2005800338784A CN200580033878A CN101035531A CN 101035531 A CN101035531 A CN 101035531A CN A2005800338784 A CNA2005800338784 A CN A2005800338784A CN 200580033878 A CN200580033878 A CN 200580033878A CN 101035531 A CN101035531 A CN 101035531A
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chemical compound
alkyl
benzoylamide
thiazolyl
halogen
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CN101035531B (en
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让·弗朗科依斯·罗西诺尔
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Romark Laboratories LC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals

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  • Thiazole And Isothizaole Compounds (AREA)

Abstract

A halogenated benzamide derivative characterized by greater specificity for viral pathogens and less disruptive to beneficial gut microflora, according to formula (III): in which R1 is a halogen atom, and R<sub A halogenated benzamide derivative characterized by greater specificity for viral pathogens and less disruptive to beneficial gut microflora, according to formula (III): in which R1 is a halogen atom, and R<SUB>2</SUB> -R<SUB>6</SUB> are independently hydrogen, hydroxyl, C<SUB>1</SUB> -C<SUB>4</SUB> alkyl, -C<SUB>1</SUB>-C<SUB>4</SUB> alkoxy, acyloxy, nitro, halogen, -C(O)R<SUB>7</SUB> where R7 is -C1-C4 alkyl, or aromatic including salts and hydrates of these compounds.

Description

Halogenated benzamide derivatives
Invention field
The present invention relates to halogenated benzamide derivatives, especially being the heterocyclic carbamate derivatives of feature to the higher specificity of virus causing disease and to the lower destructiveness of useful gastroinestinal microflora.
Background of invention
Known 2-acetyl group oxygen base-N-(5-nitro-2-thiazolyl) Benzoylamide (chemical compound of general formula (I) also is known as nitrothiazole, nitazoxanide or NTZ) is used to parasitic infection; bacterial infection, fungal infection, the treatment and the prevention (U.S. Patent number 3 of diarrhoea and other intestinal tract diseases; 950,351,4; 315,018 and 5,578; 621); comprise the processing (U.S. Patent number 5,856,348) of trematodiasis.The preparation method of NTZ is disclosed in United States Patent (USP) 3,950, in 351.The improved pharmaceutical composition that is used to send NTZ is disclosed in United States Patent (USP) 6,117, in 894 and 5,968,961.
Figure A20058003387800051
By inference, the model of action of NTZ in anaerobe and protozoon is based on the reduction of nitroreductase to nitryl group, and, especially depending on the electron transfer reaction of acetone acid ferrodoxins oxidoreductase (PFOR), this reaction is that the anaerobism energy metabolism is necessary.NTZ is also unknown to the possible model of action of anthelmintic at present, yet the enzyme of anaerobism electron transport is considered to potential target spot, and wherein, the 5-nitryl group relates to this mechanism of action.
The compound exhibits antiviral activity of known general formula (II), and be used for the treatment of human by the caused disease of virus, as by human cytomegalic inclusion disease virus, varicella-zoster, Epstein Barr virus, caused those diseases of HSV-I and HSV-II, wherein, R 1-5In one be-OH R 1-5In remaining is H (U.S. Patent number 5,886,013 and 6,020,353).
These chemical compounds are not only selective to virus causing disease when onset.Also have to describe and say that they are to parasite, antibacterial and fungus have good effect.In practice, usually be accompanied by problem.Specifically, in the gastrointestinal tract of human and a lot of animals, contain microbiota group useful, that mainly constitute by anaerobe.Those wide spectrum chemical compounds shown in the oral for example general formula (II) kill gastrointestinal bacterial flora, may cause to comprise diarrheal secondary complication, need further treat.
Therefore, need optionally treat and use chemical compound having more virus causing disease.Most preferably, these chemical compounds should have antiviral activity, but lack antibacterium and parasiticide activity basically, reach such degree at least, promptly avoid the illeffects to useful gastrointestinal microorganisms fauna when oral.
The present invention can reach this demand, so that surpass this demand, after having read following discloses content and embodiment, these all will become clear as those of ordinary skill in the art.
Summary of the invention
The present invention relates to antiviral heterocyclic carbamate derivatives, described heterocyclic carbamate derivatives has more selectivity to virus causing disease, and causes when oral illeffects to the reduction of useful gastrointestinal microorganisms fauna thus.
In first aspect, the present invention surprisingly replaces nitro substituent with halogen atom and finishes, and nitro substituent still is considered to the active key of NTZ so far.This replacement can occur in any known on effective 2-benzamido-5 nitros-thiazole (thizaole) (wherein on the phenyl ring various replacements can be arranged) in the treatment.Uncommon is that novel halogenated compound has kept their ntiviral characteristic, but bacillary gastrointestinal microorganisms fauna is lacked active when oral.
These known 2-benzamido-5 nitros-thiazoles are analog of The compounds of this invention, difference only is to be removed and to have been replaced by halogen atom according to nitryl group in the chemical compound of the present invention, the example of these known 2-benzamido-5 nitros-thiazoles is at above-mentioned United States Patent (USP), particularly U.S. Patent number 5,886, at large illustrated in 013, these openly are merged in this paper as a reference.
The present invention further provides (5-halo-2-thiazolyl) benzamide compounds as general formula (III):
Figure A20058003387800071
Wherein
R 1Be halogen atom, preferred F, Cl, Br, or I, more preferably Br or Cl most preferably are Br, and
R 2-R 6Be hydrogen independently, hydroxyl, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy (preferred acetoxyl group or propionyloxy), nitro, halogen ,-C (O) R 7, R wherein 7For-C 1-C 4Alkyl, or aromatic radical (preferred phenyl or the benzyl that does not replace or replace) comprises the salt and the hydrate of these chemical compounds.
Preferably, R 2-R 6In one be hydroxyl.
Preferably, R 2-R 6In at least one be not hydrogen, and more preferably, R 2-R 6In at least two be not hydrogen.
Two adjacent R 2-R 6Can form benzyl rings jointly.
Preferably, R 2-R 6Comprise the acyloxy that is no more than and be no more than one halogen.
The present invention further provides antiviral compound as general formula (IV):
R wherein 1Be halogen atom, R 8Be-C (O) R 10, R wherein 10Be-C 1-C 4Alkyl, and R 9Be-C 1-C 4Alkyl or-C 1-C 4Alkoxyl comprises the salt and the hydrate of these chemical compounds.
The present invention further provides the pharmaceutical composition that comprises general formula (III) or chemical compound (IV) and pharmaceutically acceptable carrier.
At last, the invention provides the method for viral infection among treatment or the prevention animal or human class experimenter, described method comprises the pharmaceutical composition that gives described at least one dosage of experimenter, described pharmaceutical composition comprise effective dose as general formula (III) or antiviral compound (IV) and pharmaceutically acceptable carrier.
Describe in detail
Chemical compound of the present invention comprises those chemical compounds as general formula (III):
Figure A20058003387800081
Wherein
R 1Be halogen atom, F preferably, Cl, Br or I, more preferably Br or Cl, Br most preferably, and
R 2-R 6Be hydrogen independently, hydroxyl, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy (being preferably acetoxyl group or propionyloxy), nitro, halogen ,-C (O) R 7, its R 7For-C 1-C 4Alkyl, or aromatic radical (preferred phenyl or benzyl, phenyl or benzyl can further be replaced) comprise the salt and the hydrate of these chemical compounds.
Preferably, R 2-R 6In a hydroxyl.
Preferably, R 2-R 6In at least one be not hydrogen, and more preferably, R 2-R 6In at least two be not hydrogen.
Two adjacent R 2-R 6Can form a benzyl rings jointly.
Preferably, R 2-R 6Comprise the halogen that is no more than one acyloxy and is no more than.Chemical compound of the present invention is illustrated by following nonrestrictive tabulation:
Figure A20058003387800082
Preferred examples of compounds comprises in the general formula (III):
2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803);
2-hydroxy-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4819);
2-acetyl group oxygen base-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4820);
2-acetyl group oxygen base-5-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4821); And
2-acetyl group oxygen base-5-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4822).
Find that also the chemical compound that has hydroxyl to replace at the phenyl ring ortho position has good effect.Therefore, from above-described chemical compound, following compounds is preferred: RM-4819, RM-4826, RM-4827, RM-4831, RM-4832, RM-4833, RM-4834, RM-4835, RM-4836, RM-4838, RM-4839, RM-4840.
Preferably include those chemical compounds of general formula (IV) according to chemical compound of the present invention:
Figure A20058003387800111
Wherein:
R 1Be halogen, preferred F, Cl, Br or I, more preferably Br or Cl, Br most preferably,
R 8Be-C (O) R 10, R wherein 10Be-C 1-C 4Alkyl.R 10Comprise methyl, ethyl, propyl group and butyl comprise their isomer.Methyl is preferred, and thus, the substituent group of described Benzoylamide is an acetyl group oxygen base (acetolyloxy), and
R 9Be-C 1-C 4Alkyl or-C 1-C 4Alkoxyl.Methyl or methoxy is preferred.Methyl is most preferred.
Examples for compounds comprises in the general formula (IV):
2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803);
2-acetyl group oxygen base-3-methyl-N-(5-chloro-2-thiazolyl) Benzoylamide (RM4804); And
2-acetyl group oxygen base-3-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4806).
Compositions of the present invention can be formulated into solid or liquid dosage form, or is formulated into paste or ointment, and can randomly comprise other active component.
Pharmaceutical composition of the present invention comprises pharmaceutically acceptable carrier, described carrier is not particularly limited, and comprise the known far-ranging carrier of those of ordinary skill in the art, and comprise wetting agent and dispersant (United States Patent (USP) 5,578,621), starch derivatives (United States Patent (USP) 5,578,621), excipient and like that.The embodiment of tablet can randomly comprise the coating of the material that constitutes enteric coating, for example, in gastric secretions insoluble basically and in intestinal juice soluble basically coating.
The pharmaceutical composition that comprises general formula (III) or chemical compound (IV) preferably is used for oral by preparation, and randomly with the form of liquid, Emulsion or solution or the suspensoid in water or oil or other liquid for example, and described oil is Oleum Arachidis hypogaeae semen for example.The preparation of nonaqueous phase micellar solution can be according to United States Patent (USP) 5,169, and disclosed method is carried out in 846.Alternatively can make tablet, for example be undertaken: wet granulation by following steps; Dry; And compacting.The film coating generally carries out with organic solvent.
Term used herein " selective antivirus " is meant, prevent or treat under the effective dose of the disease that causes by virus being used to, its activity is that antivirus action is stronger than antibacterium, antifungal or parasiticide effect, and experimenter's gastrointestinal fauna is not corrupted to the degree of using broad ectrum antibiotic to estimate.
The dosage of preferred antiviral therapy of The compounds of this invention or prevention can depend on experimenter's body weight, and can determine with reference to following examples by those of ordinary skill in the art, and need not over-drastic experimentation, the proposition of embodiment is in order to set forth clear rather than will to provide constraints.
Embodiment 1: the virus experiment
Method
Non-hepatic disorder virus
Cell culture and treatment.With the HEp-2 laryngeal cancer cell, monkey-kidney cells 37RC, MA104 and VERO cell, Canis familiaris L. Madin-Darby kidney (canine Madin-Darby kidney) (MDCK) and breast cancer cell (A72) in 37 ℃, 5%CO 2(CA) middle growth replenishes 10% hyclone (FCS), 2mM glutamine and antibiotic for Gibco-Invitrogen, Carsbad for atmosphere, RPMI culture medium.The chemical compound that will be dissolved in the DMSO storage liquid (50mg/m1) dilutes in culture medium, and adds immediately in the infected cell after the adsorption cycle at 1 hour.Remain in the culture medium at the experimental session chemical compound.The DMSO diluent of equivalent is also used in control experiment.Every kind of chemical compound tests twice under each concentration, each experiment also repeats twice.
Viral infection and titration.Use following virus: influenza A type: Peurto Rican strain (PR8); Paramyxovirus (parainfluenza virus): Sendai virus (SV); Rhabdovirus: vesicular stomatitis virus (VSV); Rotavirus: monkey rotavirus SA-11 (SA-11); Herpes simplex types 1 virus: F1 strain (HSV-1); Coronavirus: canine coronavirus S-378 strain (CCoV).Under 37 ℃, be 5HAU (hemagglutinating-unit)/10 in infection multiplicity (m.o.i.) 5During cell, converge cell monolayer in blocks 1 hour with influenza A type virus (mdck cell) or paramyxovirus SV (37RC cell) infection.Alternatively under 37 ℃, with HSV-1 (HEp-2 cell), VSV (MA104 cell), CCoV (A72 cell) or rotavirus SA-11 (MA104 cell) infect and converge cell monolayer in blocks 1 hour, HSV-1 wherein, the m.o.i. of VSV and CCoV is 5PFU (plaque forming unit)/10 5Cell, SA-11 are 1PFU/10 5Cell.After the adsorption cycle, remove the virus inoculation body, wash cell monolayer three times with phosphate buffered saline(PBS) (PBS).Cell is stored under 37 ℃ in the appropriate culture medium that contains 2%FCS, chemical compound or the contrast diluent of detected are arranged in the culture medium.Infect back (p.i.) 24 hours and determine virus yield with hemagglutinin titrimetry (WSN, PR8, SV and SA-11) or 50%CPE analytic process (VSV, HSV-1 and CCoV), definite reference standard program (Amici, C., the Belardo of described virus yield, G., Rossi, A.﹠amp; Santoro, the M.G.1 herpes simplex virus type activates I kappa b kinase, the novel targets of herpes therapy.J.Biol.Chem.276,28759-28766 (2001) and Bernasconi, D., Amici, C., La Frazia, S., Ianaro, A.﹠amp; Santoro, M.G.I kappa b kinase cause the key factor that is produced by the viral-induced airway epithelia cell inflammatory cytochine of influenza A type.J.Biol.Chem.280，24127-24134(2005))。
Cytotoxicity.Cytoactive is by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) measure with MTT first Za (formazan) transfer test (Sigma-Aldrich, St Louis, MO).In MTT test, under two different wave lengths, measure (540 and 690nm) by the ELISA microplate reader by adding acid isopropyl alcohol that 100 μ l contain 10%Triton X-100 extracts reduced form MTT (Jia Za) ， Jia Za from cell absorbance.
Hepatitis B virus
The analysis of anti--hepatitis B virus (HBV) and Cytotoxic assessment are undertaken by test in 9 days in people's hepatoblastoma cell line 2.2.15 of chronic generation HBV, as previously mentioned (Korba, B.E.﹠amp; Gerin, J.L. use the activity of standardized cell culture test assessment nucleic acid analog to hepatitis B virus duplication.Antivir.Res.19，55-70(1992))。
Hepatitis C virus
The analysis of anti--hepatitis C virus (HCV) and Cytotoxic assessment are carried out (Okuse, C., Rinaudo, J.A., Farrar, K., Wells, F.﹠amp by test in 3 days in comprising people's hepatoblastoma cell line AVA5 of HCV replicon; Korba, B.E. is by the antiviral activity of the external booster injection of interferon combined therapy to hepatitis C virus.Antivir.Res.65,23-34 (2005)), (Blight, K.J., Kolykhalov, A.A.﹠amp as the said mistake in front; Rice, C.M., effective initiation of HCV rna replicon in the cell culture.Science 290，1972-1974(2000))。
The virus testing result
Table 1. in cell culture RM-4803 and RM-4819 to the activity of virus.
Virus EC 50(μM)/SI
RM4819 RM4803 Cell culture
Rotavirus: monkey rotavirus SA-11 influenza A: PR8 strain paramyxovirus: sendai virus coronavirus: canine coronavirus S-378 strain rhabdovirus: vesicular stomatitis virus herpes simplex types 1 virus: F1 strain 0.3/＞500 9.6/＞17 1.3/＞125 4.9/＞33 1.6/＞100 0.6/＞250 0.06/＞2500 2.8/＞50 1.1/＞125 4.2/13 2.8/＞50 5.6/3 MA104 MDCK 37RC A72 MA104 HEp-2
EC 50=drug level (with respect to the average level in the culture that is untreated) when observing viral DNA or RNA 2-and doubly preventing.CC 50=with respect to the average level in the culture that is untreated, the drug level when observing reduced form MTT 2-and doubly preventing.SI (selectivity index)=CC 50/ EC 50
Table 2. in cell culture other chemical compounds to paramyxovirus: the activity of Sendai virus.
Chemical compound Paramyxovirus: Sendai virus
EC 50(μM) SI
RM-4820 RM-4821 RM-4822 0.34 0.36 0.36 35 ＞50 7
EC 50=drug level (with respect to the average level in the culture that is untreated) when observing viral RNA 2-and doubly preventing.
CC 50=with respect to the average level in the culture that is untreated, the drug level when observing reduced form MTT 2-and doubly preventing.
SI (selectivity index)=CC 50/ EC 50
Table 3. in the 2.2.15 cell culture chemical compound to the activity of hbv replication.
Chemical compound Extracellular virion DNA HBV R.I. in the cell CC 50 (μM) Selectivity index
EC 50(μM) EC 90(μM) EC 50(μM) EC 90(μM) Virion R.I.
Lamivudine RM4803 RM4819 0.058±0.006 6.3±0.7 3.5±0.5 0.164±0.015 15±1.1 9.0±0.8 0.172±0.020 12±1.5 7.6±0.9 0.660±0.068 50±5.5 22±2.6 2229±76 ＞1000 § ＞1000 § 12959 ＞67 ＞111 3377 ＞20 ＞46
Shown in numerical value (± standard deviation [S.D.]), adopt the data of the combination take from all treated cultures to calculate by linear regression analysis.S.D. by linear regression analysis (QuattroPro TM) the recurrence standard error that generates calculates.EC 50, EC 90=observe HBV DNA to be respectively 2-doubly or the drug level (with respect to average level in be untreated culture) of 10-when doubly preventing.CC 50=with respect to the average level in the culture that is untreated, the drug level when observing the dimethyl diaminophenazine chloride dyestuff and absorbing 2-and doubly prevent.Because the 3-at least of HBV level prevents doubly that normally to obtain statistical significance desired in this pilot system, therefore uses EC 90Value calculate selectivity index [S.I.].HBV dna replication dna intermediate in the HBV R.I.=cell.
§ does not observe significant cytotoxicity when reaching the Highest Directives concentration.
Table 4. in the AVA5 cell culture chemical compound to the activity of hepatitis c viral replication.
Chemical compound CC 50(μM) EC 50(μM) EC 90(μM) Selectivity index
∝-interferon ribavirin ＞10,000 *§ 61±2.9 2.2±0.2 * 94±10 8.5±0.6 * ＞100 § ＞4,545 0.6
RM4803 RM4819 282±21 164±18 37±2.7 8.9±0.7 98±9.3 79±8.2 7.6 18
Shown in numerical value (± standard deviation [S.D.]), adopt the data of the combination take from all treated cultures to calculate by linear regression analysis.S.D. by linear regression analysis (QuattroPro TM) the recurrence standard error that generates calculates.EC 50, EC 90=observe that HCV RNA is respectively that 2-doubly prevents or the drug level (with respect to average level in be untreated culture) of 10-when doubly preventing.CC 50=with respect to the average level in the culture that is untreated, the drug level when observing the dimethyl diaminophenazine chloride dyestuff and absorbing 2-and doubly prevent.Selectivity index=CC 50/ EC 50
*The value of interferon is represented as " IU/ml ".
§Do not observe significant cytotoxicity or antivirus action when reaching the Highest Directives concentration.
Embodiment 2: anaerobe detects
Method.Recently Clinical Anaerobic Bacteria separator (from 2000 so far) comprises 40 kinds of bacteroides fragilises (B.fragilis) group, 26 kinds of Pu Liwo bacterium/porphyrin Pseudomonas (Prevotella/Porphyromonas), 28 kinds of Fusobacterium doors, 16 kinds of anaerobism Gram-positive coccuses, 14 kinds of non-spore of anaerobism Gram-positive form bacillus and 18 kinds of clostridiums.Employing utilizes enrichment Brucella blood agar and 1 * 10 5The CLSI agar dilution MIC method of the inoculum that cfu/ is ordered.Place the anaerobism glove box under 35 ℃ to cultivate 48 hours culture plate.
The result.MIC 50/ MIC 90Value (μ g/ml) is as follows:
Medicine Bacteroides fragilis group (40) Pu Liwo bacterium/porphyrin Pseudomonas (26) Fusobacterium door (28) Gram-positive coccus (16) Gram-positive bacillus (14) Clostridium (18) All (142)
Nitazoxanide 2/4 4/8 1/4 0.5/2 16/＞32 0.5/4 2/4
Tizoxanide 2/4 2/16 0.5/2 0.5/1 8/＞32 0.25/2 2/4
RM 4803 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32
RM 4819 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32 ＞32/＞32
Amoxicillin with clavulanic acid 1/4 0.06/0.5 0.5/4 0.125/0.5 0.25/1.0 0.125/1.0 0.5/2.0
Clindamycin 2/＞32 ≤0.015/ ≤0.015 0.06/0.125 0.125/0.5 0.125/4 1/＞32 0.125/8.0
Metronidazole 1/2 0.5/2 0.25/0.25 0.5/1.0 ＞16/＞16 0.25/2 1.0/2.0
The result shows that except the Gram-positive anaerobic bacillus(cillus anaerobicus) that comprises lactobacillus (in fact major part is a microaerobe), nitazoxanide and tizoxanide are effective to all anaerobic bacteria floras.In contrast, RM 4803 does not have remarkable activity with RM 4819.
Embodiment 3 antiviral activities
As shown in table 5, the compound exhibits in the formula of of the present invention (IV) effective antiviral activity.
Utilize respectively many circulations CPE inhibition test to the cell monolayer of OH-I Hela and Madin Darby Testis et Pentis Canis dirty (MDCK); measured 2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803) by micro-and spectrophotometer method; 2-acetyl group oxygen base-3-methyl-N-(5-chloro-2-thiazolyl) Benzoylamide (RM4804) and 2-acetyl group oxygen base-3-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4806) are to 39 type human rhinovirus (HRV-39) and H3N2 influenza virus; the A type, EC 50(μ g/mL) value.Pirodavir (Pirodavir) and Ao Sitawei (Oseltamivir) are included in wherein as positive control.
Table 5. is RM-4803 in cell monolayer, and RM-4804 and RM-4806 are to the activity of virus.
Chemical compound 39 type human rhinovirus OH-Hela 2%McCoys+Hepes buffer microspectrophotometers Influenza A type virus MDCK 0%EMEM+Hepes+ trypsin microspectrophotometer
R 1=bromine R 4=methyl R 3=methyl (RM 4803) 0.06 0.03 0.45 0.18
R 1=chlorine R 4=methyl R 3=methyl (RM 4804) 0.57 0.32 0.93 0.57
R 1=bromine R 4=methyl R 3=methoxyl group (RM 4806) 5.0 4.0 0.46 0.57
Pirodavir 0.007 0.004 NA NA
Ao Sitawei NA NA 0.13-0.17 0.08-0.36
Embodiment 4-selective antivirus activity
At trichomonas vaginitis (Trichomis vaginalis), Giardia lamblia (Giardia Intestinalis) and trypanosoma bocagei (Trypanosoma brucei) detect the chemical compound as general formula (IV) that marks above by conventional means.2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803); in 2-acetyl group oxygen base-3-methyl-N-(5-chloro-2-thiazolyl) Benzoylamide (RM4804) and 2-acetyl group oxygen base-3-methoxyl group-N-(the 5-bromo-2-thiazolyl) Benzoylamide (RM4806) each does not all show to trichomonas vaginitis the parasiticide activity of Giardia lamblia and trypanosoma bocagei when concentration is at least 50 μ g/mL.
Therefore, verified, can provide generally with antiviral activity optionally according to the present invention be the new compound of feature.
As attendant advantages, have been found that protozoon is effective in the above-mentioned halogenated benzamides pair cell, protozoon comprises Cryptosporidium (Cryptosporidium spp.) in the said cell, new spore Eimeria (Neospora spp.) and Sarcocystisneurona (RM-4820, RM-4821 and RM-4822).
About above description, should be appreciated that to those skilled in the art it is clear and tangible that preparation of the present invention and method are considered to, all identity relations of describing in the description should be included by the present invention.
Therefore, the above is regarded as merely the explanation of the principle of the invention.In addition, the present invention should not be confined to shown and described precision architecture and operational approach, because to those skilled in the art, will a large amount of improvement and change take place easily, therefore, improvement that all are suitable and equivalent can be fallen into scope of the present invention by involution.
Quoted some list of references, patent and other publications herein, the instruction and the scope of the described publication of each part all are merged in this paper as a reference with integral body.

Claims (21)

1. chemical compound as general formula (III):
Figure A2005800338780002C1
Wherein
R 1Be halogen atom, and
R 2-R 6Be hydrogen independently, hydroxyl, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy, nitro, halogen ,-C (O) R 7, R wherein 7Be-C 1-C 4Alkyl, or aromatic radical comprise the salt and the hydrate of these chemical compounds.
2. chemical compound as claimed in claim 1, wherein R 2-R 6In at least one be not hydrogen.
3. chemical compound as claimed in claim 1, wherein R 2-R 6In at least one be hydroxyl.
4. chemical compound as claimed in claim 3, wherein said at least one hydroxyl is at the ortho position.
5. chemical compound as claimed in claim 3, wherein R 2-R 6In remaining is a hydrogen.
6. chemical compound as claimed in claim 1, wherein R 2-R 6In at least two be not hydrogen.
7. chemical compound as claimed in claim 1, wherein R 2-R 6In one be hydroxyl, R 2-R 6In remaining is hydrogen independently, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy (preferred acetoxyl group or propionyloxy), nitro, halogen ,-C (O) R 7, R wherein 7Be-C 1-C 4Alkyl, or aromatic radical comprise the salt and the hydrate of these chemical compounds.
8. chemical compound as claimed in claim 1, wherein R 2-R 6In one be hydroxyl, R 2-R 6In at least one be C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy, nitro, halogen ,-C (O) R 7, R wherein 7For-C 1-C 4Alkyl, or aromatic radical comprise the salt and the hydrate of these chemical compounds.
9. chemical compound as claimed in claim 1, wherein said acyloxy are acetoxyl group or propionyloxy, and wherein said aromatic radical is phenyl or benzyl, and this phenyl or benzyl can further be replaced.
10. chemical compound as claimed in claim 1, wherein R 1Be Br or Cl.
11. chemical compound as claimed in claim 1, wherein R 2-R 6Comprise the acyloxy that is no more than and be no more than one halogen.
12. chemical compound as claimed in claim 1, wherein two adjacent R 2-R 6Form benzyl rings.
13. chemical compound as claimed in claim 1, wherein R 2-R 6In one be hydroxyl, R 2-R 6In remaining is hydrogen independently, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy, or-C (O) R 7, R wherein 7Be-C 1-C 4Alkyl comprises the salt and the hydrate of these chemical compounds.
14. chemical compound as claimed in claim 1, described chemical compound is selected from the group of being made up of following chemical compound:
2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803);
2-hydroxy-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4819);
2-acetyl group oxygen base-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4820);
2-acetyl group oxygen base-5-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4821); And
2-acetyl group oxygen base-5-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4822).
15. the chemical compound shown in general formula (IV):
Figure A2005800338780003C1
Wherein
R 1Be halogen,
R 8Be-C (O) R 10, R wherein 10Be-C 1-C 4Alkyl, and
R 9Be-C 1-C 4Alkyl or-C 1-C 4Alkoxyl.
16. as the chemical compound of claim 14, wherein R 1Be Cl or Br.
17. as the chemical compound of claim 14, wherein R 8Be-C (O) R 10, R wherein 10Be methyl, ethyl, propyl group or butyl comprise their isomer.
18. as the chemical compound of claim 14, wherein R 9It is methyl or methoxy.
19. as the chemical compound of claim 14, described chemical compound is selected from the group of being made up of following chemical compound:
2-acetyl group oxygen base-3-methyl-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4803);
2-acetyl group oxygen base-3-methyl-N-(5-chloro-2-thiazolyl) Benzoylamide (RM4804); And
2-acetyl group oxygen base-3-methoxyl group-N-(5-bromo-2-thiazolyl) Benzoylamide (RM4806).
20. a pharmaceutical composition, described pharmaceutical composition comprise the chemical compound as general formula (III) as activating agent:
Figure A2005800338780004C1
Wherein
R 1Be halogen atom, and
R 2-R 6Be hydrogen independently, hydroxyl, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy, nitro, halogen ,-C (O) R 7, R wherein 7Be-C 1-C 4Alkyl, or aromatic radical comprise the salt and the hydrate of these chemical compounds.
21. a method for the treatment of viral infection comprises the pharmaceutical composition of experimenter's effective dose that needs treatment, described pharmaceutical composition comprises the chemical compound as general formula (III) as activating agent:
Wherein
R 1Be halogen atom, and
R 2-R 6Be hydrogen independently, hydroxyl, C 1-C 4Alkyl ,-C 1-C 4Alkoxyl, acyloxy, nitro, halogen ,-C (O) R 7, R wherein 7Be-C 1-C 4Alkyl, or aromatic radical comprise the salt and the hydrate of these chemical compounds.
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